FoxO1, A2M, and TGF-β1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses

Abstract

To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues “omics” approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-β1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful ‘hypothesis-free’ approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

“…Cldn5-related repressive transcription factor Foxo1 expression is reduced in the NAc endothelial cells of RES mice which could represent a compensatory change to prevent cldn5 loss. Interestingly, FOXO1 was recently identified as a gene predictor of depression in gene × environment interactions taking into account early life traumatic experiences (18). In our human cohort, we observed an increase of FOXO1 expression in the NAc of depressed patients, reinforcing possible involvement of this transcription factor in mood disorders.…”

“…Interestingly, FoxO1 was recently proposed as a novel gene predictor of depression in gene × environment interactions (18). On the other hand, β-catenin mediates stress resilience through modulation of microRNAs in NAc medium spiny neurons (19).…”

The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders

“…The mTORC1 pathway, which is a key signaling pathway in the effectiveness of antidepressants (64), was found to underlie the behavioral effects of resolvins (36,49). Similar findings were presented for the MAPK/ERK pathway and PI3K/Akt and AMPA signaling (36), which are involved in cell growth and proliferation and can influence the expression of proteins associated with gene × environment interactions in depression (65). Moreover, all of these are key elements involved in neurogenesis (66), which is impaired by pro-inflammatory cytokines (67) and has been shown to be rescued by n-3 PUFAs treatment after IL-1β challenge in vitro (68).…”

Nutritional and immunological factors in breast milk: A role in the intergenerational transmission from maternal psychopathology to child development

“…Great emphasis has been given to biological changes occurring during the gestational period, with particular focus on those associated with perinatal stress. Indeed, experience of excessive stress during pregnancy can expose the foetus to high level of cortisol (Reynolds, 2013), and induce epigenetic changes of genes involved in the stress (Cecil et al, 2015;Mulligan et al, 2012), and immune response (Cattaneo et al, 2018;Vaiserman, 2015), ultimately contributing to a long term impact on infant development (Bronson and Bale, 2015). Alternatively, other evidence coming from studies investigating the role of postpartum maternal care on child development has proposed maladaptive parenting as a causative determinant for the association between perinatal psychopathologies and adverse child outcomes (Silberg and Rutter, 2002).…”